141 research outputs found
Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.
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This article is open access.Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69-2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65-1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58-4.05) and incidence (HR 2.12, 95% CI 1.42-3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14-8.61) and incidence (HR 3.29, 95% CI 2.30-4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.The presence and severity of NAFLD are associated with an increased risk and severity of CKD. Please see later in the article for the Editors' Summary.Italian Ministry of University/FIRB/MERIT RBNE08NKH7_00
Posttranscriptional Regulation of the Human LDL Receptor by the U2-Spliceosome
Background: The low-density lipoprotein receptor (LDLR) in the liver is the major determinant of LDL-cholesterol levels in human plasma. The discovery of genes that regulate the activity of LDLR helps to identify pathomechanisms of hypercholesterolemia and novel therapeutic targets against atherosclerotic cardiovascular disease.Methods: We performed a genome-wide RNA interference screen for genes limiting the uptake of fluorescent LDL into Huh-7 hepatocarcinoma cells. Top hit genes were validated by in vitro experiments as well as analyses of datasets on gene expression and variants in human populations.Results: The knockdown of 54 genes significantly inhibited LDL uptake. Fifteen of them encode for components or interactors of the U2-spliceosome. Knocking down any one of 11 out of 15 genes resulted in the selective retention of intron 3 of LDLR. The translated LDLR fragment lacks 88% of the full length LDLR and is detectable neither in non-transfected cells nor in human plasma. The hepatic expression of the intron 3 retention transcript is increased in non-alcoholic fatty liver disease as well as after bariatric surgery. Its expression in blood cells correlates with LDL-cholesterol and age. Single nucleotide polymorphisms and three rare variants of one spliceosome gene, RBM25, are associated with LDL-cholesterol in the population and familial hypercholesterolemia, respectively. Compared to overexpression of wild type RBM25, overexpression of the three rare RBM25 mutants in Huh-7 cells led to lower LDL uptake.Conclusions: We identified a novel mechanism of post-transcriptional regulation of LDLR activity in humans and associations of genetic variants of RBM25 with LDL-cholesterol levels.</p
Association of Adipose tissue inflammation with histologic severity of nonalcoholic fatty liver disease
BACKGROUND & AIMS : The prevalence of nonalcoholic fatty
liver disease (NAFLD) has increased with the obesity pandemic.
We analyzed the transcriptional profiles of subcutaneous adipose
tissue (SAT) and visceral adipose tissue (VAT), and phenotypes
and functional characteristics of adipocyte tissue
macrophages (ATMs), in obese patients undergoing bariatric
surgery. METHODS : We collected anthropometric data; plasma
samples; and SAT, VAT, and liver tissues from 113 obese patients
undergoing bariatric surgery at academic hospitals in
Europe (Antwerp and Leuven) and South Africa. Based on
clinical and histologic features, patients were assigned to the
following groups: obese, NAFLD, nonalcoholic steatohepatitis
(NASH), or NASH with fibrosis. Microarray analyses were performed
to identify genes expressed differentially among groups.
We measured levels of cytokines and chemokines in plasma
samples and levels of RNAs in adipose tissues by quantitative
reverse-transcription polymerase chain reaction. ATMs were
isolated from patients and 13 lean individuals undergoing
cholecystectomy (controls), analyzed by flow cytometry, and
cultured; immunophenotypes and levels of cytokines and chemokines
in supernatants were determined. RESULTS : We
observed increased expression of genes that regulate inflammation
in adipose tissues from patients with NAFLD and NASH;
expression of these genes increased as disease progressed from
NAFLD to NASH. We found 111 genes associated with inflammation
that were expressed differentially between VAT and
SAT. Serum levels of interleukin 8, chemokine (C-C motif)
ligand 3, and tumor necrosis factor-a correlated with liver
inflammation and NAFLD activity score. We developed 2
models that could be used to determine patients’ liver histology
based on gene expression in VAT and SAT. Flow cytometry
showed increased proportions of CD11cþCD206þ and CCR2þ
macrophages in VAT from patients with NASH, and supernatants
of cultured macrophages had increased levels of cytokines
and chemokines compared with controls. CONCLUSIONS : VAT
and SAT from patients with NAFLD and NASH have an
increased expression of genes that regulate inflammation, and
ATM produce increased levels of inflammatory cytokines,
compared with adipose tissues from controls. We identified an expression profile of 5 genes in SAT that accurately predict
liver histology in these patients. Transcript profiling: accession
numbers: GSE58979 and GSE59045.Schalk van der Merwe, Chantal Mathieu, Frederik Nevens, David Cassiman, and Sven Francque are recipients of the Flanders fund for scientific research
(FWO klinisch mandaat), and Hannelie Korf is a recipient of the FWO postdoctoral mandate. Research at the Department of Endocrinology, Diabetology
and Metabolism and the Department of Gastroenterology and Hepatology of the Antwerp University Hospital (Belgium) was supported by the European
Union: FP6 (HEPADIP contract LSHM-CT-2005-018734) and FP7-HEALTH (RESOLVE no. 305707). Supported by a fellowship from the South African
Gastroenterology Association and a scholarship from the European Association for the Study of the Liver (J.d.P.). This research also was supported by a
research grant from the Gastro foundation of South Africa. The authors specifically acknowledge the support of Dr. Chris Kassianides. Also funded in part
by a grant from the Deutsche Forschungsgemeinschaft DFG-SFB 1052/1: Obesity Mechanisms (projects A04) and by the Helmholtz Alliance Imaging and
Curing Environmental Metabolic Disease through the Initiative and Networking Fund of the Helmholtz Association (M.G.).http://www.journals.elsevier.com/gastroenterology2016-09-30hb2016Internal Medicin
Features of non-alcoholic hepatic steatosis in obesity : diagnostic, pathophysiological and therapeutic aspects
The role of visceral adipose tissue in the pathogenesis of non-alcoholic fatty liver disease
Plasma adiponectin level is inversely correlated with albuminuria in overweight and obese nondiabetic individuals
Prediction of non-alcoholic fatty-liver disease and liver fat content by serum molecular lipids
PAI-1 activity, but not fibrinogen or von Willebrand factor, is inversely retated to LDL particte size in type 2 diabetes
Visceral adipose tissue and inflammation correlate with elevated liver tests in a cohort of overweight and obese patients
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